Mutations in EFHC1 cause juvenile myoclonic epilepsy

Toshimits Suzuki; Antonio Delgado-Escueta V; Kripamoy Aguan; Maria E. Alonso; Jun Shi; Yuji Haras; Motohiro Nishidas; Tomohiro Numata; Marco T. Medina; Tamaki Takeuchi; Ryoji Morita; Dongsheng Bai; Subramaniam Ganesh; Yoshihisa Sugimoto; Johji Inazawa; Julia N. Bailey; Adriana Ochoa; Aurelio Jara-Prado; Astrid Rasmussen; Jaime Ramos-Peek; Sergio Cordova; Francisco Rubio-Donnadieu; Yushi Inoue; Makiko Osawa; Sunao Kaneko; Hirokazu Oguni; Yasuo Mori; Kazuhiro Yamakawa

doi:10.1038/ng1393

Mutations in EFHC1 cause juvenile myoclonic epilepsy

Toshimits Suzuki, Antonio Delgado-Escueta V, Kripamoy Aguan, Maria E. Alonso, Jun Shi, Yuji Haras, Motohiro Nishidas, Tomohiro Numata, Marco T. Medina, Tamaki Takeuchi, Ryoji Morita, Dongsheng Bai, Subramaniam Ganesh, Yoshihisa Sugimoto, Johji Inazawa, Julia N. Bailey, Adriana Ochoa, Aurelio Jara-Prado, Astrid Rasmussen, Jaime Ramos-PeekSergio Cordova, Francisco Rubio-Donnadieu, Yushi Inoue, Makiko Osawa, Sunao Kaneko, Hirokazu Oguni, Yasuo Mori, Kazuhiro Yamakawa

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Abstract

Juvenile myoclonic epilepsy (JME) is the most frequent cause of hereditary grand mal seizures^1,2. We previously mapped and narrowed a region associated with JME on chromosome 6p12-p11 (EJM1)^3-5. Here, we describe a new gene in this region, EFHC1, which encodes a protein with an EF-hand motif. Mutation analyses identified five missense mutations in EFHC1 that cosegregated with epilepsy or EEG polyspike wave in affected members of six unrelated families with JME and did not occur in 382 control individuals. Overexpression of EFHC1 in mouse hippocampal primary culture neurons induced apoptosis that was significantly lowered by the mutations. Apoptosis was specifically suppressed by SNX-482, an antagonist of R-type voltage-dependent Ca²⁺ channel (Ca_v2.3). EFHC1 and Ca_v2.3 immunomaterials overlapped in mouse brain, and EFHC1 coimmunoprecipitated with the Ca_v2.3 C terminus. In patch-clamp analysis, EFHC1 specifically increased R-type Ca²⁺ currents that were reversed by the mutations associated with JME.

Original language	English
Pages (from-to)	842-849
Number of pages	8
Journal	Nature genetics
Volume	36
Issue number	8
DOIs	https://doi.org/10.1038/ng1393
Publication status	Published - Aug 2004
Externally published	Yes

All Science Journal Classification (ASJC) codes

Genetics

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Suzuki, T., Delgado-Escueta V, A., Aguan, K., Alonso, M. E., Shi, J., Haras, Y., Nishidas, M., Numata, T., Medina, M. T., Takeuchi, T., Morita, R., Bai, D., Ganesh, S., Sugimoto, Y., Inazawa, J., Bailey, J. N., Ochoa, A., Jara-Prado, A., Rasmussen, A., ... Yamakawa, K. (2004). Mutations in EFHC1 cause juvenile myoclonic epilepsy. Nature genetics, 36(8), 842-849. https://doi.org/10.1038/ng1393

Suzuki, T, Delgado-Escueta V, A, Aguan, K, Alonso, ME, Shi, J, Haras, Y, Nishidas, M, Numata, T, Medina, MT, Takeuchi, T, Morita, R, Bai, D, Ganesh, S, Sugimoto, Y, Inazawa, J, Bailey, JN, Ochoa, A, Jara-Prado, A, Rasmussen, A, Ramos-Peek, J, Cordova, S, Rubio-Donnadieu, F, Inoue, Y, Osawa, M, Kaneko, S, Oguni, H, Mori, Y & Yamakawa, K 2004, 'Mutations in EFHC1 cause juvenile myoclonic epilepsy', Nature genetics, vol. 36, no. 8, pp. 842-849. https://doi.org/10.1038/ng1393

@article{913250dbb4f64de2aa76b7b0d5c8d8b2,

title = "Mutations in EFHC1 cause juvenile myoclonic epilepsy",

abstract = "Juvenile myoclonic epilepsy (JME) is the most frequent cause of hereditary grand mal seizures1,2. We previously mapped and narrowed a region associated with JME on chromosome 6p12-p11 (EJM1)3-5. Here, we describe a new gene in this region, EFHC1, which encodes a protein with an EF-hand motif. Mutation analyses identified five missense mutations in EFHC1 that cosegregated with epilepsy or EEG polyspike wave in affected members of six unrelated families with JME and did not occur in 382 control individuals. Overexpression of EFHC1 in mouse hippocampal primary culture neurons induced apoptosis that was significantly lowered by the mutations. Apoptosis was specifically suppressed by SNX-482, an antagonist of R-type voltage-dependent Ca2+ channel (Cav2.3). EFHC1 and Cav2.3 immunomaterials overlapped in mouse brain, and EFHC1 coimmunoprecipitated with the Cav2.3 C terminus. In patch-clamp analysis, EFHC1 specifically increased R-type Ca2+ currents that were reversed by the mutations associated with JME.",

author = "Toshimits Suzuki and {Delgado-Escueta V}, Antonio and Kripamoy Aguan and Alonso, {Maria E.} and Jun Shi and Yuji Haras and Motohiro Nishidas and Tomohiro Numata and Medina, {Marco T.} and Tamaki Takeuchi and Ryoji Morita and Dongsheng Bai and Subramaniam Ganesh and Yoshihisa Sugimoto and Johji Inazawa and Bailey, {Julia N.} and Adriana Ochoa and Aurelio Jara-Prado and Astrid Rasmussen and Jaime Ramos-Peek and Sergio Cordova and Francisco Rubio-Donnadieu and Yushi Inoue and Makiko Osawa and Sunao Kaneko and Hirokazu Oguni and Yasuo Mori and Kazuhiro Yamakawa",

note = "Funding Information: We thank the family members for participating in this study; Y. Itsukaichi, K. Yamada, Y. Tsutsumi, K. Shoda, E. Mazaki, A. Nitta, N. Okamura, C. Uchikawa, M. Hishinuma and S.G. Pietsch for their help; and the Research Resources Center of RIKEN Brain Science Institute for DNA sequencing analysis and generation of rabbit polyclonal antibodies. This work was supported in part by a grant from RIKEN Brain Science Institute, Japan. A.V.D.E. is partly supported by a grant from the US National Institutes of Health.",

year = "2004",

month = aug,

doi = "10.1038/ng1393",

language = "English",

volume = "36",

pages = "842--849",

journal = "Nature Genetics",

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T1 - Mutations in EFHC1 cause juvenile myoclonic epilepsy

AU - Suzuki, Toshimits

AU - Delgado-Escueta V, Antonio

AU - Aguan, Kripamoy

AU - Alonso, Maria E.

AU - Shi, Jun

AU - Haras, Yuji

AU - Nishidas, Motohiro

AU - Numata, Tomohiro

AU - Medina, Marco T.

AU - Takeuchi, Tamaki

AU - Morita, Ryoji

AU - Bai, Dongsheng

AU - Ganesh, Subramaniam

AU - Sugimoto, Yoshihisa

AU - Inazawa, Johji

AU - Bailey, Julia N.

AU - Ochoa, Adriana

AU - Jara-Prado, Aurelio

AU - Rasmussen, Astrid

AU - Ramos-Peek, Jaime

AU - Cordova, Sergio

AU - Rubio-Donnadieu, Francisco

AU - Inoue, Yushi

AU - Osawa, Makiko

AU - Kaneko, Sunao

AU - Oguni, Hirokazu

AU - Mori, Yasuo

AU - Yamakawa, Kazuhiro

N1 - Funding Information: We thank the family members for participating in this study; Y. Itsukaichi, K. Yamada, Y. Tsutsumi, K. Shoda, E. Mazaki, A. Nitta, N. Okamura, C. Uchikawa, M. Hishinuma and S.G. Pietsch for their help; and the Research Resources Center of RIKEN Brain Science Institute for DNA sequencing analysis and generation of rabbit polyclonal antibodies. This work was supported in part by a grant from RIKEN Brain Science Institute, Japan. A.V.D.E. is partly supported by a grant from the US National Institutes of Health.

PY - 2004/8

Y1 - 2004/8

N2 - Juvenile myoclonic epilepsy (JME) is the most frequent cause of hereditary grand mal seizures1,2. We previously mapped and narrowed a region associated with JME on chromosome 6p12-p11 (EJM1)3-5. Here, we describe a new gene in this region, EFHC1, which encodes a protein with an EF-hand motif. Mutation analyses identified five missense mutations in EFHC1 that cosegregated with epilepsy or EEG polyspike wave in affected members of six unrelated families with JME and did not occur in 382 control individuals. Overexpression of EFHC1 in mouse hippocampal primary culture neurons induced apoptosis that was significantly lowered by the mutations. Apoptosis was specifically suppressed by SNX-482, an antagonist of R-type voltage-dependent Ca2+ channel (Cav2.3). EFHC1 and Cav2.3 immunomaterials overlapped in mouse brain, and EFHC1 coimmunoprecipitated with the Cav2.3 C terminus. In patch-clamp analysis, EFHC1 specifically increased R-type Ca2+ currents that were reversed by the mutations associated with JME.

AB - Juvenile myoclonic epilepsy (JME) is the most frequent cause of hereditary grand mal seizures1,2. We previously mapped and narrowed a region associated with JME on chromosome 6p12-p11 (EJM1)3-5. Here, we describe a new gene in this region, EFHC1, which encodes a protein with an EF-hand motif. Mutation analyses identified five missense mutations in EFHC1 that cosegregated with epilepsy or EEG polyspike wave in affected members of six unrelated families with JME and did not occur in 382 control individuals. Overexpression of EFHC1 in mouse hippocampal primary culture neurons induced apoptosis that was significantly lowered by the mutations. Apoptosis was specifically suppressed by SNX-482, an antagonist of R-type voltage-dependent Ca2+ channel (Cav2.3). EFHC1 and Cav2.3 immunomaterials overlapped in mouse brain, and EFHC1 coimmunoprecipitated with the Cav2.3 C terminus. In patch-clamp analysis, EFHC1 specifically increased R-type Ca2+ currents that were reversed by the mutations associated with JME.

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JF - Nature Genetics

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Mutations in EFHC1 cause juvenile myoclonic epilepsy

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